CN101896488A - Prepare the mutter method of salt of normorphine - Google Patents

Prepare the mutter method of salt of normorphine Download PDF

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Publication number
CN101896488A
CN101896488A CN2008801207825A CN200880120782A CN101896488A CN 101896488 A CN101896488 A CN 101896488A CN 2008801207825 A CN2008801207825 A CN 2008801207825A CN 200880120782 A CN200880120782 A CN 200880120782A CN 101896488 A CN101896488 A CN 101896488A
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alkyl
replacement
compound
aryl
thiazolinyl
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彼得·X·王
江涛
加里·L·坎特雷尔
戴维·W·伯布里克
博比·N·特拉威克
鲍健
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Mallinckrodt Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides the OPIOIDS derivative is converted into the mutter method of compound of normorphine, this normorphine compound of muttering is used for preparation " receiving " compound analgesic agent and antagonist.Particularly, this method can be used for preparing the pure normorphine salt of muttering from thick OPIOIDS substrate.

Description

Prepare the mutter method of salt of normorphine
The cross reference of related application
The application requires the right of priority of the provisional application sequence number 61/014,105 of submission on December 17th, 2007, and it is hereby incorporated by with its integral body.
Technical field
The present invention relates generally to from thick OPIOIDS (opioid) substrate and prepares the mutter method of salt of pure normorphine.
Background technology
Removing the first oxymorphone is the morphinan intermediate that is used to prepare important " receiving (the nal) " compound of a series of biology, comprises TREXUPONT, naloxone, Nalmefene and nalbuphine.Along with increase to the demand of these APIs (active pharmaceutical ingredient), for more effective and more the preparation of high purity ground go the first oxymorphone that bigger demand is arranged.
All the time, go the first oxymorphone by in water, going the first oxymorphone to obtain in 30 to 40 hours at 95 to 110 ℃ of hydrolysis dec-with 30-40% sulfuric acid.Referring to, for example, " Noroxymorphone frommorphine. " Wallace, Rebecca A. (Mallinckrodt, Inc., USA) .Eur.Pat.Appl.EP158476 (1985).Some problems relevant with this method are arranged, comprising: (a) raw material (being that dec-removes first oxymorphone (dec-noroxymorphone)) has the solvability of non-constant; (b) hydrolysis rate very slow (reaction will spend 30 to 40 hours and finish); (c) oxidation characteristic of hydrolytic reagent (being sulfuric acid) and heating that the required prolongation of hydrolysis takes place cause the decomposition of first oxymorphone product; With, (d) total reaction causes the productive rate of first oxymorphone low and impurity is high.Therefore the OPIOIDS derivative need be converted into the method that crucial being used to prepares the morphinan compound of analgesic agent and antagonist.
Summary of the invention
One aspect of the present invention comprises the method for preparing compound 2 according to following reaction from compound 1:
Figure GPA00001159277700021
Wherein:
R 1Be selected from hydrogen, the alkyl of alkyl and replacement;
R 1aBe the oxygen protecting group;
R 2Be selected from the alkyl of alkyl and replacement;
R 3, R 4, R 5And R 6Be independently selected from hydrogen, halogen, hydroxyl, methoxyl group, {-} OR 8, the alkyl of alkyl and replacement;
R 8Be selected from the alkyl of alkyl and replacement; With
X is the halogen that is selected from Cl and Br.
The present invention provides the method for preparing compound 3 according to following reaction from compound 2 on the other hand:
Figure GPA00001159277700022
Wherein:
R 1Be selected from hydrogen, the alkyl of alkyl and replacement;
R 1aBe the oxygen protecting group;
R 2Be selected from the alkyl of alkyl and replacement;
R 3, R 4, R 5And R 6Be independently selected from hydrogen, halogen, hydroxyl, {-} OR 8, the alkyl of alkyl and replacement;
R 7Be selected from the pKa that has less than about 0 protophobe;
R 8Be selected from the alkyl of alkyl and replacement; With
X is the halogen that is selected from Cl and Br.
The present invention provides the two-stage process of preparation compound 3 on the other hand.This method comprises first reaction, and this first reaction comprises compound 1 and proton acceptor and XCO 2R 2Contact is to form compound 2.In second reaction, compound 2 contacts with protophobe with formation compound 3, as following reaction scheme:
Figure GPA00001159277700031
Wherein:
R 1Be selected from hydrogen, the alkyl of alkyl and replacement;
R 1aBe the oxygen protecting group;
R 2Be selected from the alkyl of alkyl and replacement;
R 3, R 4, R 5And R 6Be independently selected from hydrogen, halogen, hydroxyl, {-} OR 8, the alkyl of alkyl and replacement;
R 7Be selected from the pKa that has less than about 0 protophobe;
R 8Be selected from the alkyl of alkyl and replacement; With
X is the halogen that is selected from Cl and Br.
Others of the present invention and be described in following more detailed description.
Detailed Description Of The Invention
Found the OPIOIDS derivative is converted into the mutter method of compound of normorphine, this normorphine compound of muttering is used for preparation " receiving " compound analgesic agent and antagonist.Particularly, this method can be used for preparing the pure normorphine salt of muttering from thick OPIOIDS substrate.
This method comprises the two-step reaction scheme.In this method steps A, the OPIOIDS derivative is converted into the normorphine intermediate of muttering.Although use the solvent replacing system, advantageously, normorphine is muttered and be separated into solid in the whole route of synthesis that intermediate need not describe in reaction scheme 1.In the step B of this method, this normorphine intermediate of muttering is hydrolyzed with the preparation crystallization normorphine salt of muttering.For explanatory purpose, reaction scheme 1 has been described according to an aspect of the present invention from compound 1 (that is OPIOIDS derivative) preparation compound 3 (that is, normorphine mutter salt):
Figure GPA00001159277700051
Wherein:
R 1Be selected from hydrogen, the alkyl of alkyl and replacement;
R 1aBe the oxygen protecting group;
R 2Be selected from the alkyl of alkyl and replacement;
R 3, R 4, R 5And R 6Be independently selected from hydrogen, halogen, hydroxyl, methoxyl group, {-} OR 8, the alkyl of alkyl and replacement;
R 7Be selected from the pKa that has less than about 0 protophobe;
R 8Be selected from the alkyl of alkyl and replacement; With
X is the halogen that is selected from Cl and Br.
In an exemplary, the substituting group of reaction scheme 1 comprises:
R 1Be selected from hydrogen, acyl group, alkyl, thiazolinyl, aryl, the alkyl of replacement, the thiazolinyl of replacement, the aryl of replacement and alkoxy carbonyl;
R 2Be selected from alkyl, thiazolinyl, aryl, the alkyl of replacement, the thiazolinyl of replacement and the aryl of replacement;
R 3, R 4, R 5And R 6Be independently selected from hydrogen, halogen, hydroxyl, acyl group, alkyl, thiazolinyl, aryl, the alkyl of replacement, the thiazolinyl of replacement, the aryl of replacement, alkoxy carbonyl, carbonyl;
R 7Be selected from sulfuric acid, methylsulfonic acid, toluenesulphonic acids, phosphoric acid, hydrochloric acid and Hydrogen bromide; With
X is a chlorine.
(I) steps A: compound 1 is to the conversion of compound 2
This method steps A is included under the existence of proton acceptor OPIOIDS derivative (compound 1) and XCO 2R 2Contact is to form one or more normorphines intermediate (compound 2) of muttering.Then reaction mixture is used the protonic solvent cancellation, and by product is removed from reaction mixture by washing step.Then reaction mixture is carried out the solvent replacing step.
(a) Reaction parameter
Usually, be used for preparing the compound 1 of the substrate of compound 2 corresponding to reaction scheme 1 description.In an exemplary, compound 1 is selected from oxymorphone, oxycodone, hydrocodone, hydromorphone and these compounds derivative separately.When compound 1 comprises oxymorphone, R 1Be hydrogen, R 3, R 4And R 5The hydrogen of respectively doing for oneself; And R 6Be hydroxyl.Perhaps when compound 1 comprises oxycodone, R 1Be methyl, R 3, R 4And R 5The hydrogen of respectively doing for oneself; And R 6Be hydroxyl.When compound 1 comprises hydrocodone, R 1Be methyl, R 3, R 4And R 5The hydrogen of respectively doing for oneself; And R 6Be hydrogen.Perhaps when compound 1 comprises hydromorphone, R 1Be hydrogen, R 3, R 4And R 5The hydrogen of respectively doing for oneself; And R 6Be hydrogen.
In this method steps A, compound 1 and XCO 2R 2Contact.Constitute R 2Exemplary alkyl or the alkyl of replacement comprise alkyl, thiazolinyl, aryl, the alkyl of replacement, the thiazolinyl of replacement and the aryl of replacement.Some preferred formation R 2Alkyl or the alkyl of replacement be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aminomethyl phenyl, or benzyl.For each above-mentioned embodiment, X can be chlorine or bromine.In an exemplary, X is a chlorine, and R 2Be ethyl.
This method steps A carries out in the presence of proton acceptor usually.Usually, the pKa that this proton acceptor has is about 7 to about 13, preferred about 8 to about 10.Spendable representative proton acceptor include, but not limited to borate (as, for example, NaBO 3), binary and ternary phosphates (as, for example, Na 2HPO 4And Na 3PO 4), supercarbonate (as, for example, NaHCO 3, KHCO 3, its mixture etc.), hydroxide salt (as, for example, NaOH, KOH, its mixture etc.), carbonate (as, for example, Na 2CO 3, K 2CO 3, its mixture etc.), organic proton acceptor (as, for example, pyridine, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, N, the N-dimethyl aminopyridine, and composition thereof), the organic buffer agent (as, for example, N-(2-kharophen)-2-aminoethyl sulfonic acid (ACES), N-(2-kharophen)-imido oxalic acid (ADA), N, N-two (2-hydroxyethyl) glycine (BICINE), 3-(cyclohexyl amino)-1-propanesulfonic acid (CAPS), 2-(cyclohexyl amino) ethyl sulfonic acid (CHES), 4-(2-hydroxyethyl)-1-piperazine propanesulfonic acid (EPPS), 4-(2-hydroxyethyl) piperazine-1-ethyl sulfonic acid (HEPES), 2-(4-morpholinyl) ethyl sulfonic acid (MES), 4-morpholine propanesulfonic acid (MOPS), 1,4-piperazine two ethyl sulfonic acids (PIPES), [(2-hydroxyl-1,1-two (hydroxymethyl) ethyl) amino]-1-propanesulfonic acid (TAPS), 2-[(2-hydroxyl-1,1-two (hydroxymethyl) ethyl) amino] ethyl sulfonic acid (TES), their salt and/or mixture etc.), and combination.In one embodiment, this proton acceptor is selected from NaHCO 3, KHCO 3, LiHCO 3, KHCO 3, LiHCO 3, K 2CO 3, NaOH, KOH, Na 2HPO 4/ Na 3PO 4, K 2HPO 4/ K 3PO 4, and composition thereof.In a preferred embodiment, this proton acceptor is NaHCO 3, KHCO 3, or its combination.
The amount of the reactant that uses in this method steps A can change and will change and not depart from scope of the present invention.Usually, compound 1 and XCO 2R 2With the mol ratio of proton acceptor be about 1: 2: 1 to about 1: 20: 20.More typically, compound 1 and XCO 2R 2With the mol ratio of proton acceptor be about 1: 6: 3 to about 1: 12: 5.
This method steps A also carries out in the presence of aprotic solvent usually.Preferred proton acceptor and the XCO of selecting 2R 2Reagent is to increase compound 1 and/or the solvability of compound 2 in aprotic solvent.The limiting examples of aprotic solvent comprises ether solvents, acetonitrile, benzene, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), N, N-dimethyl propylene acid amides, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone (DMPU), 1,3-dimethyl-2-imidazolidone (DMI), 1,2-glycol dimethyl ether (DME), N,N-dimethylacetamide (DMAC), N-Methyl pyrrolidone (NMP), ethyl acetate, ethyl formate, ethyl-methyl ketone, isobutyl methyl ketone, methane amide, hexamethylphosphoramide, methyl acetate, N-methylacetamide, N-methylformamide, methylene dichloride, oil of mirbane, Nitromethane 99Min., propionitrile, tetramethylene sulfone, tetramethyl-urea, tetrahydrofuran (THF) (THF), toluene, trichloromethane.Preferred aprotic solvent can comprise chloroform, 1, and the 2-ethylene dichloride, toluene, chlorobenzene, ethyl acetate, propyl acetate, isopropyl acetate, THF, acetonitrile, and composition thereof.In an exemplary, this aprotic solvent is a chloroform.Usually, aprotic solvent is about 2: 1 (g/g) with the ratio of the amount of compound 1.
For forming reaction mixture, adding XCO usually 2R 2Before compound 1 and solvent are merged with proton acceptor.Perhaps, yet, solvent, XCO 2R 2Can mix with proton acceptor, be added into afterwards in the reaction vessel of inclusion compound 1.
The temperature of the reaction mixture of this method steps A usually about 50 ℃ to about 80 ℃ scope.More typically, this reaction will be carried out to about 65 ℃ temperature at about 55 ℃.This reaction also can be carried out in environmental stress or inert atmosphere (for example, nitrogen or argon gas).
Usually, reaction is carried out time enough up to reacting completely, (for example, HPLC) measure by chromatography.In this article, each amount of substance when " reaction completely " typically refers to than the reaction beginning, reaction mixture comprises the reactant of remarkable reduction and the product of remarkable increasing amount.Usually, this reaction is carried out about 1 hour to about 48 hours, and more typically, carries out about 9 hours to about 15 hours.
After reaction is finished, the cancellation in protonic solvent usually of this reaction mixture.Exemplary proton solvent is a water.At this moment, this reaction mixture is separated into two-layer usually: organic layer and water layer.
(b) Remove by product and surplus stock
It will be understood by those skilled in the art that one or more undesirable by products produce usually in steps A.In this article, term " undesirable by product " comprises compound, and this compound does not comprise formula 2.This by product can change and will change according to chemical constitution and other reactant of substrate (that is, compound 1).As an example, when compound 1 comprised oxymorphone, main by product can comprise 3-O-ethoxy carbonyl oxymorphone and 3-O-, 14-O-di ethoxy carbonyl oxymorphone and composition thereof.Perhaps when compound 1 comprised oxycodone, main by product can comprise 14-O-ethoxy carbonyl oxycodone.Perhaps when compound 1 comprised hydromorphone, main by product can comprise 3-O-ethoxy carbonyl hydromorphone.
For increasing the end product productive rate and the purity of compound 2 and final compound 3, usually by product is removed basically from reaction mixture.In an exemplary, this by product can be removed from reaction mixture by washing step.This washing step generally includes and the organic layer of reaction mixture (as above described in (Ia)) and pH are lower than 7 acid proton solvent contact.In an exemplary, this acid proton solvent will be about 0.1 to about 2.0 sour water for pH.At organic layer with behind the acid proton solvent wash, but physical removal and abandon the water layer that comprises a large amount of by products.This washing step can repeat to be about 2 to about 10 times, and more preferably, about 3 to about 6 times.
Usually, behind the washing step in the organic layer remaining by product comprise about 0.01% organic layer to about 2% area/area, and in an exemplary, remaining by product can comprise the organic layer less than about 0.5% area/area in the organic layer.Usually, behind the washing step in the organic layer amount of remaining compound 2 account for organic layer about 80% to about 99% area/area.In exemplary, behind the washing step in the organic layer amount of remaining compound 2 be at least 90%, at least 95%, at least 97% of organic layer, or greater than 99% area/area.
(c) solvent replacing
This reaction mixture can be carried out the solvent replacing process, being another kind with a kind of solvent replacing.In this article, second solvent can be added into reaction mixture, and the solvent that exists in the reaction mixture can pass through solvent replacing method (for example distillation is directly replaced, or saltoutd) removal.In using the process of this solvent replacing method, normorphine is muttered does not need to be separated into solid in the whole route of synthesis process that intermediate (that is, compound 2) describes in reaction scheme 1.Although the process that can in (Ia), describe in detail at last reaction mixture is carried out solvent replacing, in an exemplary, reaction mixture carried out in (Ib) washing step that describes in detail before solvent replacing.
Usually, can use second solvent that reaction mixture is carried out solvent replacing to reduce or to replace the aprotic solvent (being called " first solvent " in this section) of use in (Ia).In an exemplary, the solvent replacing method is distillation, and is preferably vacuum distilling.This second solvent has higher boiling point usually with first solvent phase ratio.Because second solvent has the boiling point higher than first solvent, this first solvent can be replaced by distillation.The second suitable solvent comprises the alcohol of 3 to 8 carbon atoms and the protophobe of 2 to 8 carbon atoms.Exemplary solvent is right, for example, can comprise chloroform as first solvent and propionic acid as second solvent.In an exemplary, vacuum distilling is carried out in about 85 ℃ temperature.This still-process does not preferably need to be distilled to dried, does not therefore have solid to form usually.
(II) step B: hydrolysis compound 2 is to form compound 3
In the step B of this method, compound 2 is hydrolyzed to form compound 3.Compound 3 is the normorphine salt of muttering.In an exemplary, this normorphine salt of muttering is selected from first oxymorphone salt, removes first oxycodone salt, removes first hydrocodone salt and removes methyldihydromorphinone salt.
In the exemplary of step B, select this hydrolysing agent so that they dissolve all reactants basically in the starting stage of hydrolysis reaction.In this article, preferred reactant at least about 90% dissolved in 3 hours behind the beginning hydrolysis reaction.Because all hydrolysis reactants dissolve when hydrolysis reaction begins basically, this speed of reaction maximization, and obviously reduce of the crossed contamination of raw material reagent to product (that is, compound 3).
The hydrolysis reaction of step B is included under the existence of solvent system compound 2 is contacted with protophobe.The pKa that this protophobe has usually is less than 0.Suitable proton with this feature includes, but are not limited to MeSO 3H, poly H 3PO 4, H 3PO 4, H 2SO 4, HCl, HBr, HClO 4, HI, HNO 3, CF 3SO 3H is to methyl toluenesulphonic acids, HClO 3, HBrO 4, HIO 3And HIO 4
Compound 2 can be about 1: 1.5 to about 1: 10 with the mol ratio of protophobe.More typically, compound 2 can be about 1: 3 to about 1: 5 with the mol ratio of protophobe.
Because the method for describing in the reaction scheme 1 is carried out (that is, this hydrolysis reaction carries out usually) in a continuous manner after the solvent replacing process of (Ic), the solvent system that uses in the hydrolysis reaction generally includes the remaining solvent in distillation back.In this article, this solvent system will comprise the remaining protonic solvent in a certain amount of distillation back usually.In an exemplary, this protonic solvent comprises propionic acid.This solvent system is alternative to comprise or comprises in addition that other protonic solvent is as alcohol or other and the mixable solvent of water; Therefore, for example, protonic solvent can be water mutually, water/alcohol mixture, or water/with the mixable solvent mixture of water.The representative alcohols of water/alcohol mixture comprises, for example, and methyl alcohol, ethanol, Virahol, isopropylcarbinol, the trimethyl carbinol, n-propyl alcohol, propyl carbinol, and combination.For water/comprise with other and the mixable solvent of water of the mixable solvent mixture of water, for example, acetonitrile, N, dinethylformamide, 1-Methyl-2-Pyrrolidone, N,N-dimethylacetamide, acetone, tetrahydrofuran (THF), acetate, propionic acid, caproic acid, and combination.In an exemplary, this solvent system will comprise propionic acid and water, and described protophobe comprises MeSO 3H.
Randomly, also anti-oxidant compounds can be added into hydrolysis reaction to improve the purity of compound 3.Suitable antioxidant includes, but not limited to xitix and salt thereof, Quicifal, ascorbyl stearate, Arnold Ke Suomo (anoxomer), positive acetylcysteine, the benzyl lsothiocyanates, gavaculine, anthranilic acid, para-amino benzoic acid (paba), butyl hydroxyanisole (bha), Yoshinox BHT (bht), coffic acid, canthaxanthin (canthaxantin), alpha-carotene, β-Hu Luobusu (beta-carotene), β-Hu Luobusu (β-caraotene), β-A Piao daucic acid (apo-carotenoic acid), carnosol, isothymol, catechin, the hexadecyl gallic acid ester, chlorogenic acid, citric acid and salt thereof, Flos Caryophylli extract, coffee bean extract, P-coumaric acid, 3, the 4-resorcylic acid, N, N '-phenylbenzene-p-phenylenediamine (dppd), dilauryl thiodipropionate, distearyl thiodipropionate, 2,6-two-tert-butyl phenol, dodecyl gallic acid ester, edetic acid, ellagic acid, saccharosonic acid, SODIUM ISOVITAMIN C, Esculetin, Vitamin C2,6-oxyethyl group-1,2-dihydro-2,2, the 4-trimethylquinoline, the ethyl gallic acid ester, veltol plus, ethylenediamine tetraacetic acid (EDTA) (edta), eucalyptus extracts, Eugenol, forulic acid, flavonoid is (for example, catechin, l-Epicatechol, L-Epicatechin gallate, epigallocatechin (egc), epigallocatechin gallic acid ester (egcg), polyphenol epigallocatechin-3-gallic acid ester), flavones (for example, apigenin, chrysin, Luteolin), flavonol (for example, datiscetin, myricetin, daemfero), flavanone, fraxetin, fumaric acid, gallic acid, Radix Gentianae extract, glyconic acid, glycine, gum guaiacum, Hesperitin, Alpha-hydroxy benzyl phospho acid, hydroxycinnamic acid (hydroxycinammic acid), the hydroxyl pentanedioic acid, quinhydrones, N-hydroxy succinic acid, Hydroxytyrosol (hydroxytryrosol), hydroxyurea, rice bran extract, lactic acid and salt thereof, Yelkin TTS, the Yelkin TTS citrate; The r-alpha-lipoic acid, xenthophylls, Lyeopene, oxysuccinic acid, voitol, 5-methoxytryptamine, methyl gallic acid ester, direactive glyceride citrate; Single sec.-propyl citrate; Morin, β-naphthoflavene goes to first dihydroguaiaretic acid (ndga), the octyl group gallic acid ester, oxalic acid, palmityl citrate, thiodiphenylamine, phosphatidylcholine, phosphoric acid, phosphoric acid ester, phytic acid, phytyl ubichromanol (phytylubichromel), pimento extract, propyl gallate ester, polyphosphate, Quercetin, anti--trans-resveratrol, rosemary extract, rosmarinic acid, sage extract, sesamol, silymarin, sinapinic acid, succsinic acid, stearyl citrate, syringic acid, tartrate, thymol, tocopherol are (promptly, α-, β-, γ-and Delta-Tocopherol), tocotrienols (that is, and α-, β-, γ-and δ-tocotrienols), tyrosol, vanillic acid, 2,6-two-tertiary butyl-4-hydroxy sylvan (that is, ionox 100), 2,4-(three-3 ', 5 '-two-tertiary butyl-4 '-hydroxybenzyl)-1,3,5-Three methyl Benzene (that is, ionox 330), 2,4, the 5-THBP 2,4,5 trihydroxybutyrophenone, ubiquinone, tertiary butylated hydroquinone (tbhq), thio-2 acid, THBP 2,4,5 trihydroxybutyrophenone, tryptamines, tyrasamine, uric acid, vitamin k and derivative, VITAMIN q10, wheat germ oil, zeaxanthin, or its combination.The amount of antioxidant can be about 0.002 to about 0.02 of reaction mixture weight.
The temperature range that can carry out this reaction is about 75 ℃ to about 150 ℃.More preferably, the temperature range that can carry out this reaction is about 90 ℃ to about 115 ℃.In another embodiment, the temperature range that can carry out this reaction is about 95 ℃ to about 110 ℃.This reaction is preferably carried out under environmental stress, and preferably carries out in inert atmosphere (for example, nitrogen or argon gas).
After the hydrolysis, compound 3 forms crystalline compounds usually, and it can separate from reaction mixture as filtration and/or centrifugation by the known method of prior art.(for example, HPLC) mensuration is generally at least 90% to the purity of compound 3 by chromatography.In exemplary, the purity of compound 3 is at least 95% by chromatography determination, and at least 96%, at least 97%, at least 98%, at least 99%, or greater than 99.5%.Can be about 65% to about 85% (mol/mol) from the overall yield of the compound 3 of compound 1 preparation.
Method as herein described can be used for preparing compound, that is, compound 2 or 3, its rotation about polarized light has (-) or (+) three-dimensional chemical configuration.More specifically, each chiral centre can have R or S configuration.For being easy to discuss, the annular atoms of the parent nucleus morphinan structure that this paper mentions is by following numbering:
Figure GPA00001159277700121
As shown in the parent nucleus morphinan structure, there are four chiral carbon to comprise in any (that is, compound 1,2 or 3) of the compound that uses in the method for the invention, that is, and carbon 5,13,14 and 9.Therefore, compound 1,2 or 3 configuration can be RRRS about C5, C13, C14 and C9, SRRS, SRSS, RSRR, RSSR, SSRR or SSSR.
(III) is from the compound of compound 3 preparations
Compound itself corresponding to compound 3 can be final product, or is intermediate, this intermediate can be further in a step or multistep derivatize to generate further morphinan intermediate or final product.As limiting examples, this method can use one or more compounds corresponding to compound 3 to be selected from following compound with preparation: nalbuphine, Nalmefene, naloxone, TREXUPONT, the TREXUPONT Methobromide, the 3-O-methyl naltrexone is received bent alcohol (naltrexol), receives Lip river alcohol (naloxol), and salt, intermediate and analogue.The general reaction scheme for preparing this morphinan that commercial value is arranged especially is disclosed in the United States Patent (USP) 4,368,326 of Rice, and it is whole openly to be hereby incorporated by.
In addition, in some embodiments, the N-alkylation that can use compound 3 is to form the N-alkyl derivative of compound 3, and wherein 6-ketone is reducible is 6-α-OH, 6-β-OH, 6-α-NH 2Or 6-β-NH 2
Definition
Term " acyl group " is as using separately at this or as the part of other group, expression is removed the part that hydroxyl forms from the COOH base of organic carboxyl acid, for example, RC (O)-, wherein R is R 1, R 1O-, R 1R 2N-or R 1S-, R 1Be alkyl, assorted alkyl or the heterocyclic radical that replaces, and R 2Alkyl for hydrogen, alkyl or replacement.
Term " acyloxy ", as using separately at this or, represent aforesaid acyl group by oxygen connection (O) bonding as the part of other group, for example, RC (O) O-, wherein the same definition in R and the term " acyl group ".
Following group described in term as herein described " alkyl ", and it is preferably the low alkyl group that comprises 1 to 8 carbon atom at main chain, and be up to 20 carbon atoms.That they can be straight or branched or cyclic, and comprise methyl, ethyl, propyl group, sec.-propyl, butyl, hexyl etc.
Term as herein described " alkaryl " or " alkylaryl " have been described following group, and it is preferably the aryl with low-grade alkyl substituent, as tolyl, ethylphenyl or methyl naphthyl.
Following group described in term as herein described " thiazolinyl ", and it is preferably the low-grade alkenyl that comprises 2 to 8 carbon atoms at main chain, and be up to 20 carbon atoms.That they can be straight or branched or cyclic, and comprise vinyl, propenyl, pseudoallyl, butenyl, isobutenyl, hexenyl, etc.
Following group described in term as herein described " alkynyl ", and it is preferably the low-grade alkynyl that comprises 2 to 8 carbon atoms at main chain, and be up to 20 carbon atoms.They can be straight or branched, and comprise ethynyl, proyl, butynyl, isobutyl alkynyl, hexin base, etc.
Following group described in term as herein described " aralkyl ", and it is preferably the low alkyl group that comprises 1 to 8 carbon atom with aryl substituent, as benzyl, phenylethyl or 2-naphthyl methyl.
Term " aromatics " is as using separately at this or as the part of other group, optional homocyclic ring or the heterocyclic aromatic group that replaces of expression.These aromatic groups are preferably monocycle, dicyclo or three cyclic groups that comprise 6 to 14 atoms at loop section.Term " aromatics " comprises with undefined " aryl " and " heteroaryl ".
Term " aryl ", as using separately at this or as the part of other group, the optional homocyclic ring aromatic group that replaces of expression preferably comprises the monocycle or the bicyclic radicals of 6 to 12 carbon at loop section, as the phenyl of phenyl, xenyl, naphthyl, replacement, the xenyl of replacement or the naphthyl of replacement.The phenyl of phenyl and replacement is preferred aryl.
It is to point to container to add compound or reagent that term used herein " is filled (charged) ".
Term " halogen " or " halogen " are as using separately at this or as the part of other group, being meant chlorine, bromine, fluorine and iodine.
Term " heteroatoms " is meant the atom except carbon and hydrogen.
Term " heterocyclic radical " or " heterocycle ", as using separately at this or as the part of other group, expression is optional to be replaced, complete saturated or undersaturated, monocycle or dicyclo, aromatics or non-aromatic group, it has at least one heteroatoms at least one ring, and preferably at each ring 5 or 6 atoms is arranged.Heterocyclic radical preferably has 1 or 2 Sauerstoffatom and/or 1 to 4 nitrogen-atoms in ring, and is connected to the remainder of molecule by carbon or heteroatoms.Exemplary heterocyclic radical comprises the heteroaromatic of the following stated.Exemplary substituting group comprises one or more following groups: the hydroxyl of the alkyl of alkyl, replacement, hydroxyl, protection, acyl group, acyloxy, alkoxyl group, alkene oxygen base, alkynyloxy group, aryloxy, halogen, amide group, amino, cyano group, ketal, acetal, ester and ether.
Term " heteroaryl " is as using separately at this or as the part of other group, being illustrated in the aromatic group that at least one ring has at least one heteroatomic optional replacement, and preferably having 5 or 6 atoms at each ring.This heteroaryl preferably has 1 or 2 Sauerstoffatom and/or 1 to 4 nitrogen-atoms in ring, and is connected to the remainder of molecule by carbon.Exemplary heteroaryl comprises furyl, benzofuryl ， oxazolyl ， isoxazolyl ， oxadiazole base benzoxazolyl, Ben Bing oxadiazole base, pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indyl, pseudoindoyl, indolizine base, benzimidazolyl-, indazolyl, benzotriazole base, tetrazolo pyridazinyl, carbazyl, purine radicals, quinolyl, isoquinolyl, imidazopyridyl etc.Exemplary substituting group comprises one or more following groups: alkyl, the alkyl of replacement, hydroxyl, the hydroxyl of protection, acyl group, acyloxy, alkoxyl group, alkene oxygen base, alkynyloxy group, aryloxy, halogen, amide group, amino, cyano group, ketal, acetal, ester and ether.
Term as herein described " hydrocarbon " and " alkyl " have been described organic compound or the group only be made up of elemental carbon and hydrogen.These parts comprise alkyl, thiazolinyl, alkynyl and aryl moiety.These parts also comprise alkyl, thiazolinyl, alkynyl and the aryl moiety that is replaced by other aliphatics or cyclic hydrocarbon group, as alkaryl, and alkene aryl and alkynes aryl.Unless have describedly in addition, these parts preferably include 1 to 20 carbon atom.
" alkyl of replacement " as herein described part be the hydrocarbyl portion that is replaced by at least one non-carbon atom, comprises with the lower section, and wherein the carbochain atom is by heteroatoms such as nitrogen, oxygen, silicon, phosphorus, boron, sulphur, or halogen atom replacement.These substituting groups comprise halogen, heterocyclic radical, alkoxyl group, alkene oxygen base, aryloxy, hydroxyl, the hydroxyl of protection, acyl group, acyloxy, nitro, amino, amide group, nitro, cyano group, ketal, acetal, ester and ether.
Term used herein " hydroxyl protecting group " expression can be protected the group of free hydroxyl group (" hydroxyl of protection "), and it in reaction (this reaction is protected) afterwards, can be removed and does not influence the remainder of molecule.
When introducing the element of the present invention or its preferred embodiment, article " ", " a kind of ", " be somebody's turn to do " and " is described " to be meant and to have one or more elements.Term " comprises ", in " comprising " and " having " are interpreted as and are included in, and be meant other element that can exist outside institute's column element.
Because can carry out various changes and not depart from scope of the present invention to above-claimed cpd, product and method, should understand the material that comprises in all above-mentioned specification sheetss and following examples should be interpreted as illustrative and be not the restriction the meaning.
Embodiment
Following examples are described different aspect of the present invention.
Following examples have described in detail from the synthetic pure first oxymorphone salt that goes of thick oxymorphone.This reaction scheme is shown below:
Figure GPA00001159277700151
Synthetic for laboratory scale, this reaction vessel (reactor) is three-necked flask (that is the scale of the corresponding 0.10kg of interpolation of 1.0L flask oxymorphone).Each container is equipped with agitator, condenser, nitrogen inlet and outlet, and feed hopper.
Embodiment 1. prepares to the initial prototype of removing first oxymorphone salt from thick oxymorphone
With thick oxymorphone (actual weight of pure oxymorphone multiply by its wt/wt% by the weight with thick oxymorphone to be determined) and chloroform (CHCl 3) (oxymorphone that every kg adds 3.36kg) is added into reactor.Start agitator with reaction stirred mixture and reactor purging with nitrogen gas.Then with sodium bicarbonate (NaHCO 3) (oxymorphone that every kg adds, 1.4kg) and Vinyl chloroformate (EtOCOCl) (oxymorphone of every kg interpolation 3.74kg) is added into reactor.Up to the temperature that reaches 64 ± 2 ℃, the minimum maintenance of this temperature is 9 hours then with about 0.5 ℃/minute speed reactor heating.Reaction process is analyzed monitoring by HPLC.This reaction product comprises that dec-goes first oxymorphone (3-O-, the 17-N-di ethoxy carbonyl removes the first oxymorphone) and tec-to remove first oxymorphone (17-N-triethoxy carbonyl removes the first oxymorphone for 3-O-, 14-O-).
In case reaction is finished, mixture is cooled to temperature less than 30 ℃.For removing by product and surplus stock (that is, the EtOCO-derivative and the oxymorphone of oxymorphone) from reaction, this reaction product that contains chloroform is washed with sour water.For this stage, (oxymorphone that every kg adds 3.6L) is added into reactor, and with mixture stir about 30-45 minute with water.By adding 70% methylsulfonic acid (MeSO on demand 3H) or 50%NaOH with the pH regulator of mixture value to about 0.8-2.0.Closing agitator and making the mixture sedimentation is two-phase.Lower floor's chloroform phase transition is new reactor extremely, and abandons the upper strata water.Under the situation of agitator operation, (oxymorphone that every kg adds 2.0L) is added into chloroform phase in the new reactor, and adds 70%MeSO with water 3H or 50%NaOH reach about 0.8-2.0 up to the pH of mixture.Stop agitator, make mixture form two-phase, and with lower floor's chloroform phase transition to another reactor.Organic phase with the sour water washing once, substantially as mentioned above, and is transferred to another reactor again.
When agitator moved, (oxymorphone that every kg adds 0.75L) was added into the reactor of the chloroform phase that contains washing with propionic acid (EtCOOH).Distillation plant is installed, vacuum is put on reactor, and the temperature of this reaction mixture is increased to about 80-85 ℃ to distill solvent.In case the cumulative volume of resistates is during for about 1.8L (, the oxymorphone pact that every kg adds 1.6-2.0L), is closed valve tube and reactor is filled with nitrogen again.
Remaining mixture in reactor, and interpolation EtCOOH (oxymorphone that every kg adds, 1.0L), water (oxymorphone that every kg adds, 0.7L), 6% sulfurous acid (H 2SO 3, the oxymorphone that every kg adds, 2.0L) and 70%MeSO 3H (oxymorphone that every kg adds, 2.0L).With mixture heating up to about 107 ± 3 ℃ distilling some volatile solvents, and reaction mixture kept about 9-12 hour in this temperature.Hydrolysis reaction is monitored by HPLC.The solvent total amount that distills is the about 0.5-1.0L of oxymorphone that every kg adds, and heating crystal occurred after 3-4 hour in mixture.
In case hydrolysis reaction is finished, reaction mixture is cooled to less than 35 ℃, and adds 3.0L Virahol (IPA).Then mixture is cooled to about 5-10 ℃ and kept 1-2 hour in this temperature.By the gained suspension in the glass filter filtration reactor.In addition, this reactor 96%MeSO 3H: H 2(oxymorphone that every kg adds, cold (5-10 ℃) solution 0.5L) washes O: IPA (3: 7: 30 volume ratios), and washing fluid is transferred to glass filter.This reactor is used 96%MeSO as mentioned above 3H: H 2The solution of O: IPA washes once more, and this washing fluid also is transferred to glass filter.(oxymorphone that every kg adds, 0.5L) flushing is then by being drawn into valve tube 20 hour and drying with air by solid in room temperature with IPA for solid on the filter.Remove first oxymorphone MeSO 3The productive rate of H be 70-80%mol/mol (oxymorphone that every kg adds ,～1.0kg).If complete drying not, solid further in vacuum 80 ℃ of dryings 20 hours.
First oxymorphone salt-test 2 is gone in embodiment 2. preparations
To contain 200g oxymorphone and 460g CHCl 3Thick oxymorphone be added into reactor.Start agitator and container purging with nitrogen gas.Add 232g NaHCO to this reactor 3, then 748gEtOCOCl was added into reactor gradually through 15 minutes, keep reaction mixture to be in temperature simultaneously less than 55 ℃.After all EtOCOCl are added into reactor, with reaction mixture restir 30 minutes.Then reaction mixture is heated to about 60-65 ℃ temperature, and kept 9 hours, then in case the temperature that is cooled to less than 35 ℃ is finished in reaction in this temperature range.
The refrigerative mixture is transferred to second reactor, in second reactor, adds 400mL water simultaneously in agitator operation.Initial reactor 200mL water washing, and this water that comprises the residual reaction mixture is added into second reactor equally, and whole mixture in reactor restir 30-45 minute.In case all solids dissolving stops agitator, and to make the reaction mixture sedimentation be two-phase.Initial reactor is returned in lower floor's chloroform phase transition, starts agitator, and abandons the upper strata water in second reactor.Stir simultaneously, 300mL water is added into reaction mixture, add 70%MeSO then 3H is reduced to up to the pH of reaction mixture and is lower than 1.Again 100mL water is added into reactor, with mixture restir 15 minutes, stops agitator then, making the mixture sedimentation is two-phase.Lower floor's chloroform phase transition is returned second reactor and is started agitator, and abandons the upper strata water.
When in second reactor, stirring the mixture, add 400mL water, add the 70%MeSO of q.s then 3H (the MeSO of about 4g 3H) be reduced to value with pH less than 1 with mixture.Closing agitator then and making the mixture sedimentation is two-phase.Initial reactor is returned in lower floor's chloroform phase transition, and abandons the upper strata water.
When agitator moves, 100mL propionic acid (EtCOOH) is added into the reactor of the chloroform phase that contains washing.Distillation plant is installed, is applied the vacuum of 100mm Hg, and with the temperature of mixture be increased to about 50 ℃ to distill solvent.After mixture reached about 50 ℃ temperature, vacuum remained on the value less than 150mm, and the temperature of mixture is increased to about 85 ℃.After these conditions are kept 1 hour, vacuum is removed from reactor.
To this reactor, add 200mL EtCOOH, 300mL water, 6.6mL 6%H 2SO 3And 150mL99.5%MeSO 3H.Keep 12 hours to distill about 80-100mL volatile solvent with mixture heating up to 107 ± 1 ℃ and in this temperature.Then reaction mixture is cooled to about 0-5 ℃ temperature.
In case the temperature of this reaction mixture is brought down below 25 ℃, add 600mL IPA.When this reaction mixture reaches about 0-5 ℃ temperature, this temperature was kept about 2 hours.The gained suspension filters by glass filter, and this suspension is by using the 100mLMeSO of the temperature that is precooled to about 5-10 ℃ 3H: H 2O: IPA solution (3: 7: 30 volume ratios) washes this reactor three times and obtains.Filtering solid vacuum-drying 18 hours, causes forming white crystal about 50-60 ℃ temperature.The product productive rate of this experiment is about 75%.
First oxymorphone salt-test 3 is gone in embodiment 3. preparations
Reactor is loaded thick oxymorphone (comprising the 30g oxymorphone) and 69.1g CHCl 3Start agitator and container purging with nitrogen gas.To this reactor, add 35g NaHCO 3, then 112.6gEtOCOCl was added into reactor gradually through 15 minutes, simultaneously reaction mixture is remained on temperature less than 55 ℃.After all Vinyl chloroformates are added into reactor, with reaction mixture restir 30 minutes.Then reaction mixture is heated to about 60-65 ℃ temperature, and kept 9 hours in this temperature range.In case reaction is finished, mixture is cooled to temperature less than 35 ℃.
The refrigerative mixture is transferred to second reactor, wherein stirs 60mL water.Initial reactor 60mL water washing, and this water that comprises the residual reaction mixture is added into second reactor equally, and with whole mixture restir 30-45 minute.In case all solids dissolving stops agitator, and to make the reaction mixture sedimentation be two-phase.Initial reactor is returned in lower floor's chloroform phase transition, starts agitator, and abandons the upper strata water in second reactor.Stir simultaneously, 60mL water is added into reaction mixture, add 70%MeSO then 3H is reduced to up to the pH of reaction mixture and is lower than 1.Then agitator is stopped, making the mixture sedimentation is two-phase.Lower floor's chloroform phase transition is returned initial reactor and started agitator, and abandon the upper strata water.
In reactor, add 60mL water in the stirred mixture, add the 70%MeSO of q.s then 3H is reduced to value less than 1 with the pH with mixture.Closing agitator then and making the mixture sedimentation is two-phase.Lower floor's chloroform phase transition that will comprise di ethoxy carbonyl-go first oxymorphone and triethoxy carbonyl-remove the first oxymorphone is to another reactor, and abandons the upper strata water.
Chloroform phase in reactor is added 30mL IPA, and 15mL water adds 30gMeSO then 3H, then that the gained mixture heating up is extremely about 90 ℃ temperature is to distill CHCl 3This mixture postheating keeps above 1 hour to about 95-100 ℃ temperature and in this temperature.To mixture, add 9mL water, be heated to about 95-105 ℃ temperature then, keep 6 hours to distill more multi-solvent.Other 9mL water is added into this mixture, keeps 6 hours again to distill other solvent at 95-105 ℃ then.After mixture is cooled to 75 ℃, add 15mL water and 5mL IPA, then mixture is cooled to room temperature and kept 1 hour.Filter the gained suspension, and filtering solid 15mLMeSO 3H/H 21: 2 solution washing twice of O is used the 15mL washing with acetone 4 times then.The gained solid dry 2 days of vacuum condition, obtains the 30.6g solid product 55 ℃ temperature.
First oxymorphone salt-test 3 is gone in embodiment 4. preparations
Contain di ethoxy carbonyl-go first oxymorphone and triethoxy carbonyl-go the chloroform phase transition of first oxymorphone with what use embodiment 3 described schemes preparations to reactor.Add the 30mL trimethyl carbinol (t-BuOH), 15mL water to this mixture, add 21g MeSO then 3H.This is begun temperature be heated to about 90 ℃ temperature to distill chloroform (CHCl less than 35 ℃ of solution 3).This mixture postheating keeps above 1 hour to about 95-100 ℃ temperature and in this temperature.Add 6mL water to this mixture, be heated to about 95-105 ℃ temperature then, kept 6 hours.Other 15mL water is added into mixture, kept again 6 hours at 95-105 ℃ then.After mixture is cooled to 75 ℃, add 15mL water and 5mL IPA, then mixture is cooled to room temperature and kept 1 hour.Filter the gained suspension, and filtering solid 15mL MeSO 3H/H 21: 2 solution washing twice of O is used the 15mL washing with acetone 4 times then.The gained solid dry 2 days of vacuum condition, obtains the 30.6g solid product 55 ℃ temperature.
First oxymorphone salt-test 4 is gone in embodiment 5. preparations
The chloroform phase transition that contains di ethoxy carbonyl-go first oxymorphone and triethoxy carbonyl-remove the first oxymorphone of using embodiment 3 described schemes preparations to reactor, and is drained, obtain viscous solid.To this viscous solid, add 10mL caproic acid and 50mL water, add the 20mL vitriol oil (c-H then gradually 2SO 4).Then reaction mixture is heated to 105 ℃ temperature, and kept 2 hours in this temperature.Then mixture is cooled to 10 ℃ and kept 2 hours, and filter the gained suspension.Filtering solid 15mL MeSO 3H/H 21: 2 solution washing of O 2 times is used the 15mL washing with acetone 4 times then.The gained solid dry 2 days of vacuum condition, obtains the 24.3g solid product 55 ℃ temperature.
Embodiment 6. goes the preparation-test 5-of the improvement of first oxymorphone salt to have more high yield
Add thick oxymorphone to reactor, this reactor comprises 31g oxymorphone and 46g CHCl 3Start agitator and container purging with nitrogen gas.Add 46g NaHCO to this reactor 3, through 15 minutes the 75g Vinyl chloroformate is added into reactor gradually then, keep reaction mixture in temperature simultaneously less than 55 ℃.After all Vinyl chloroformates are added into reactor, with reaction mixture restir 30 minutes.Then reaction mixture is heated to about 60-65 ℃ temperature, and kept 9 hours in this temperature range.In case reaction is finished, mixture is cooled to temperature less than 35 ℃.
The refrigerative mixture is transferred to second reactor, in this second reactor, stirs 40mL water.Initial reactor 40mL water washing, and this water that comprises the residual reaction mixture is added into second reactor equally, and with whole mixture restir 30-45 minute.In case all solids in mixture dissolving stops agitator, and to make the reaction mixture sedimentation be two-phase.Initial reactor is returned in lower floor's chloroform phase transition, starts agitator, and abandons the upper strata water in second reactor.Stir simultaneously, 40mL water is added into reaction mixture, add enough 70%MeSO then 3H is reduced to the pH with reaction mixture and is lower than 1.Stop agitator once more, making the mixture sedimentation is two-phase.Lower floor's chloroform phase transition is returned second reactor and is started agitator, and abandons the upper strata water.Repeat to add 40mL water and MeSO 3H is reduced to less than 1 with the pH with mixture, removes the process of lower floor's chloroform phase then.Initial reactor is returned in the chloroform phase transition, and restart agitator.
When agitator moves, 10mL propionic acid (EtCOOH) is added into the reactor of the chloroform phase that contains washing.Distillation plant is installed, is applied the vacuum of 100mm Hg, and the temperature of this reaction mixture is increased to about 50 ℃.After reaching 50 ℃,, increase the temperature to 85 ℃ of mixture simultaneously to apply vacuum 15 minutes less than 150mm Hg.After mixture being reached 85 ℃ temperature, mixture is kept under the vacuum of 120mm Hg in this temperature.
Remove distillation plant (comprising vacuum), and with 20mL EtCOOH, 30mL water, 6.8g H 2SO 3With 15mL 99.5%MeSO 3H is added into mixture.With mixture heating up to 107 ± 1 ℃, and keep 12 hours to distill solvent in this temperature.Then mixture is cooled to 0-5 ℃ temperature.When mixture is less than 25 ℃ temperature, adds 60mL IPA, and the temperature of mixture at 0-5 ℃ kept 2 hours again.
Then the gained suspension is filtered by glass filter, and by using the 10mL MeSO that is precooled to 5-10 ℃ of temperature 3H/H 2The suspension of O/IPA (volume ratio 3: 7: 30) flushing reactor gained also filters by glass filter.Filtering solid under vacuum condition temperature 50-60 ℃ drying 20 hours to obtain white crystal.Remove first oxymorphone MeSO 3The productive rate of H is 82%.

Claims (15)

1. the method for preparing compound 2 according to following reaction from compound 1:
Figure FPA00001159277600011
Wherein:
R 1Be selected from the alkyl of hydrogen, alkyl and replacement;
R 1aBe the oxygen protecting group;
R 2Be selected from the alkyl of alkyl and replacement;
R 3, R 4, R 5And R 6Be independently selected from hydrogen, halogen, hydroxyl, methoxyl group, {-} OR 8, alkyl and replacement alkyl;
R 8Be selected from the alkyl of alkyl and replacement; With
X is the halogen that is selected from Cl and Br.
2. the described method of claim 1, wherein:
R 1Be selected from the alkyl of hydrogen, acyl group, alkyl, thiazolinyl, aryl, replacement, the thiazolinyl of replacement, the aryl and the alkoxy carbonyl of replacement;
R 2Be selected from the alkyl of alkyl, thiazolinyl, aryl, replacement, the thiazolinyl of replacement and the aryl of replacement;
R 3, R 4, R 5And R 6Be independently selected from the alkyl of hydrogen, halogen, hydroxyl, acyl group, alkyl, thiazolinyl, aryl, replacement, the thiazolinyl of replacement, aryl, alkoxy carbonyl and the carbonyl of replacement;
X is a chlorine.
3. each described method in the claim 1 or 2, the pKa that wherein said proton acceptor has is greater than about 7; This is reflected under the existence of aprotic solvent and carries out; Compound 1 and XCO 2R 2With the mol ratio of proton acceptor be about 1: 3: 1 to about 1: 20: 20, the temperature range of carrying out this reaction is about 50 ℃ to about 80 ℃; And compound 2 comprises the mixture that is selected from first oxymorphone derivative and removes the compound of first oxycodone derivative.
4. each described method in the claim 1 to 3, wherein said method causes forming by-product compounds, and described by-product compounds does not have formula 2, and this reaction mixture is separated into organic layer and water layer after reaction mixture is with the protonic solvent cancellation; And this by-product compounds is removed from reaction mixture by washing step, and it is that about 0.8 to about 2.0 protonic solvent contacts that this washing step comprises organic layer and pH, separates water layer from reaction mixture then.
5. the described method of claim 4, wherein said aprotic solvent is with being selected from pure and mild second solvent replacing with protophobe of 2 to 8 carbon atoms with 3 to 8 carbon atoms.
6. the method for preparing compound 3 according to following reaction from compound 2:
Figure FPA00001159277600021
Wherein:
R 1Be selected from the alkyl of hydrogen, alkyl and replacement;
R 1aBe the oxygen protecting group;
R 2Be selected from the alkyl of alkyl and replacement;
R 3, R 4, R 5And R 6Be independently selected from hydrogen, halogen, hydroxyl, {-} OR 8, alkyl and replacement alkyl;
R 7Be selected from the pKa that has less than about 0 protophobe;
R 8Be selected from the alkyl of alkyl and replacement; With
X is the halogen that is selected from Cl and Br.
7. the described method of claim 6, wherein:
R 1Be selected from the alkyl of hydrogen, acyl group, alkyl, thiazolinyl, aryl, replacement, the thiazolinyl of replacement, the aryl and the alkoxy carbonyl of replacement;
R 2Be selected from the alkyl of alkyl, thiazolinyl, aryl, replacement, the thiazolinyl of replacement and the aryl of replacement;
R 3, R 4, R 5And R 6Be independently selected from alkyl, the thiazolinyl of replacement, the aryl of replacement, alkoxy carbonyl, the carbonyl of hydrogen, halogen, hydroxyl, acyl group, alkyl, thiazolinyl, aryl, replacement;
R 7Be selected from sulfuric acid, methylsulfonic acid, toluenesulphonic acids, phosphoric acid, hydrochloric acid and Hydrogen bromide; With
X is a chlorine.
8. each described method in the claim 6 or 7, the pKa that wherein said protophobe has is less than 0, and Hydrogen bromide; This is reflected under the existence of at least a protonic solvent and carries out, protonic solvent is about 2: 1 (g/g) with the ratio of the amount of compound 2, compound 2 is about 1: 1.5 to about 1: 10 (g/g) with the mol ratio of protophobe, and is reflected at about 90 ℃ and carries out to about 115 ℃ temperature range.
9. the method for preparing compound 3, this method comprise that first reaction comprises compound 1 and proton acceptor and XCO according to first reaction of following reaction scheme and second reaction 2R 2Contact comprises compound 2 is contacted with protophobe with formation compound 3 to form compound 2, the second reactions:
Figure FPA00001159277600041
Wherein:
R 1Be selected from the alkyl of hydrogen, alkyl and replacement;
R 1aBe the oxygen protecting group;
R 2Be selected from the alkyl of alkyl and replacement;
R 3, R 4, R 5And R 6Be independently selected from hydrogen, halogen, hydroxyl, {-} OR 8, alkyl and replacement alkyl;
R 7Be selected from the pKa that has less than about 0 protophobe;
R 8Be selected from the alkyl of alkyl and replacement; With
X is the halogen that is selected from Cl and Br.
10. the described method of claim 9, wherein:
R 1Be selected from the alkyl of hydrogen, acyl group, alkyl, thiazolinyl, aryl, replacement, the thiazolinyl of replacement, the aryl and the alkoxy carbonyl of replacement;
R 2Be selected from the alkyl of alkyl, thiazolinyl, aryl, replacement, the thiazolinyl of replacement and the aryl of replacement;
R 3, R 4, R 5And R 6Be independently selected from alkyl, the thiazolinyl of replacement, the aryl of replacement, alkoxy carbonyl, the carbonyl of hydrogen, halogen, hydroxyl, acyl group, alkyl, thiazolinyl, aryl, replacement;
R 7Be selected from sulfuric acid, methylsulfonic acid, toluenesulphonic acids, phosphoric acid, hydrochloric acid and Hydrogen bromide; With
X is a chlorine.
11. each described method in claim 9 or 10, the pKa that wherein said proton acceptor has is greater than about 7; And first is reflected under the existence of aprotic solvent and carries out; Compound 1 and XCO 2R 2With the mol ratio of proton acceptor be about 1: 3: 1 to about 1: 20: 20, this first is reflected at about 50 ℃ and carries out to about 80 ℃ temperature range; Compound 2 comprises the mixture that is selected from first oxymorphone derivative and removes the compound of first oxycodone derivative; The pKa that this protophobe has is less than 0; This second is reflected under the existence of at least a protonic solvent and carries out, protonic solvent is about 2: 1 (g/g) with the ratio of the amount of compound 2, compound 2 is about 1: 1.5 to about 1: 10 (g/g) with the mol ratio of protophobe, and second is reflected at about 90 ℃ and carries out to about 115 ℃ temperature range.
12. each described method in the claim 9 to 11, wherein said method causes forming by-product compounds, and described by-product compounds does not have formula 2, and this reaction mixture is separated into organic layer and water layer after reaction mixture is with the protonic solvent cancellation; And this by-product compounds is removed from reaction mixture by washing step, and it is that about 0.8 to about 2.0 protonic solvent contacts that this washing step comprises organic layer and pH, separates water layer from reaction mixture then.
13. the described method of claim 12, wherein said aprotic solvent is with being selected from pure and mild second solvent replacing with protophobe of 2 to 8 carbon atoms with 3 to 8 carbon atoms.
14. each described method in the claim 9 to 13, wherein compound 3 forms crystal; The productive rate of compound 3 is about 65% to about 85% (mol/mol); The purity of compound 3 is at least 95% by chromatography determination.
15. each described method in the claim 9 to 14, wherein compound 1,2 or 3 optical activity are selected from (-) enantiomer, (+) enantiomer, and combination; And compound 1,2 or 3 separately carbon 5,13,14 and 9 configuration be selected from RRRS, RRSS, SRRS, SRSS, RSRR, RSSR, SSRR and SSSR.
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Publication number Priority date Publication date Assignee Title
US3905981A (en) * 1973-10-12 1975-09-16 Research Corp N-dealkylation of tertiary amines
US4141897A (en) * 1976-12-20 1979-02-27 Research Corporation N-dealkylation of N-alkyl-14-hydroxymorphinans and derivatives thereof
US4368326A (en) 1980-07-03 1983-01-11 Rice Kenner C Short total synthesis of dihydrothebainone, dihydrocodeinone, and nordihydroccodeinone
FR2562072B1 (en) * 1984-03-27 1989-07-07 Mallinckrodt Inc PROCESS FOR THE PREPARATION OF NOROXYMORPHONE FROM MORPHINE, AND INTERMEDIATE COMPOUNDS USED IN THIS PROCESS
FR2564838B1 (en) * 1984-05-25 1986-11-07 Sanofi Sa PROCESS FOR DEALKYLATION OF ALKALOIDS AND INTERMEDIATES
US4994069A (en) * 1988-11-02 1991-02-19 Target Therapeutics Vaso-occlusion coil and method
US5122136A (en) * 1990-03-13 1992-06-16 The Regents Of The University Of California Endovascular electrolytically detachable guidewire tip for the electroformation of thrombus in arteries, veins, aneurysms, vascular malformations and arteriovenous fistulas
US5354295A (en) * 1990-03-13 1994-10-11 Target Therapeutics, Inc. In an endovascular electrolytically detachable wire and tip for the formation of thrombus in arteries, veins, aneurysms, vascular malformations and arteriovenous fistulas
DE4104702C2 (en) * 1991-02-15 1996-01-18 Malte Neuss Implants for organ pathways in spiral form
US5690666A (en) * 1992-11-18 1997-11-25 Target Therapeutics, Inc. Ultrasoft embolism coils and process for using them
US5690671A (en) * 1994-12-13 1997-11-25 Micro Interventional Systems, Inc. Embolic elements and methods and apparatus for their delivery
DE69624525T2 (en) * 1995-03-30 2003-03-20 Boston Scient Ltd System for implanting liquid spirals with a secondary structure
NO962336L (en) * 1995-06-06 1996-12-09 Target Therapeutics Inc Vaso-occlusive spiral
US6013084A (en) * 1995-06-30 2000-01-11 Target Therapeutics, Inc. Stretch resistant vaso-occlusive coils (II)
DK0754435T3 (en) * 1995-06-30 2000-11-27 Target Therapeutics Inc Stretch-resistant co-occlusion spirals
US5582619A (en) * 1995-06-30 1996-12-10 Target Therapeutics, Inc. Stretch resistant vaso-occlusive coils
US5749894A (en) * 1996-01-18 1998-05-12 Target Therapeutics, Inc. Aneurysm closure method
US5792154A (en) * 1996-04-10 1998-08-11 Target Therapeutics, Inc. Soft-ended fibered micro vaso-occlusive devices
US5853413A (en) * 1997-04-18 1998-12-29 Bristol-Myers Squibb Company Wrist fusion plate
US5984929A (en) * 1997-08-29 1999-11-16 Target Therapeutics, Inc. Fast detaching electronically isolated implant
US6156061A (en) * 1997-08-29 2000-12-05 Target Therapeutics, Inc. Fast-detaching electrically insulated implant
US6322576B1 (en) * 1997-08-29 2001-11-27 Target Therapeutics, Inc. Stable coil designs
US5941888A (en) * 1998-02-18 1999-08-24 Target Therapeutics, Inc. Vaso-occlusive member assembly with multiple detaching points
US5980550A (en) * 1998-06-18 1999-11-09 Target Therapeutics, Inc. Water-soluble coating for bioactive vasoocclusive devices
US6187024B1 (en) * 1998-11-10 2001-02-13 Target Therapeutics, Inc. Bioactive coating for vaso-occlusive devices
US6179857B1 (en) * 1999-02-22 2001-01-30 Cordis Corporation Stretch resistant embolic coil with variable stiffness
US6280457B1 (en) * 1999-06-04 2001-08-28 Scimed Life Systems, Inc. Polymer covered vaso-occlusive devices and methods of producing such devices
WO2006084389A1 (en) * 2005-02-11 2006-08-17 Cilag Ltd. Method for purifying noroxymorphone compounds
GB2471802B (en) * 2006-05-25 2011-02-16 Alpharma Chemical process

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WO2009078989A1 (en) 2009-06-25
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AU2008338971B2 (en) 2013-08-29
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